Tissue culture-adapted, mouse brain-adapted and natural street rabies virus (RV) strains such as the silver-haired bat-associated strain (SHBRV) differ greatly in their pathogenicity. Although we have shown that the rabies (RV) glycoprotein (RV G) is a major player in the pathogenesis of rabies, our knowledge of molecular mechanisms involved in the pathogenesis of rabies is still not complete. The cryptic human rabies cases caused by SHBRV typify the gap in our understanding of rabies pathogenesis, which is most likely a multigenic trait involving several RV-encoded proteins and transcriptional elements, as well as host factors. Therefore, we will continue using reverse genetics technology to identify elements of the RV genome that are responsible for the unique ability of this street RV not only to enter the CNS from a peripheral site but also to cause invariably lethal neurological disease. We have shown that RV G induces de novo protein synthesis, along with apoptosis. Based on these findings, we speculate that expression of RV G can cause a dramatic change in cell functions and thereby could play a central role in RV pathogenesis. Consequently, we will investigate the mechanism(s) by which the RV G induces host cell gene expression. Results from these studies will have practical implications for the development of safer and more efficacious live rabies vaccines, and will provide further basic information on rabies virus pathogenicity. This information could lead to the development of novel therapeutic strategies against clinical rabies. This is particularly significant in view of the increasing number of human rabies cases where exposure to RV is not recognized and, therefore, conventional post-exposure prophylaxis is not initiated sufficiently early to be effective.